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WO2017208209A1 - Compositions pharmaceutiques nasales à excipient poreux - Google Patents

Compositions pharmaceutiques nasales à excipient poreux Download PDF

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Publication number
WO2017208209A1
WO2017208209A1 PCT/IB2017/053288 IB2017053288W WO2017208209A1 WO 2017208209 A1 WO2017208209 A1 WO 2017208209A1 IB 2017053288 W IB2017053288 W IB 2017053288W WO 2017208209 A1 WO2017208209 A1 WO 2017208209A1
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WO
WIPO (PCT)
Prior art keywords
active agent
composition
condition
testosterone
porous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2017/053288
Other languages
English (en)
Inventor
Claudia Mattern
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
M&P Pharma AG
Original Assignee
M&P Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP17731299.8A priority Critical patent/EP3463375A1/fr
Priority to SG11201810628XA priority patent/SG11201810628XA/en
Priority to CN201780047958.8A priority patent/CN109803663A/zh
Priority to KR1020197000033A priority patent/KR102387241B1/ko
Priority to CA3026041A priority patent/CA3026041A1/fr
Priority to EA201892595A priority patent/EA201892595A1/ru
Priority to JP2019516293A priority patent/JP7542309B2/ja
Priority to AU2017274649A priority patent/AU2017274649B2/en
Application filed by M&P Pharma AG filed Critical M&P Pharma AG
Priority to MX2018014906A priority patent/MX389588B/es
Publication of WO2017208209A1 publication Critical patent/WO2017208209A1/fr
Anticipated expiration legal-status Critical
Priority to ZA2018/08551A priority patent/ZA201808551B/en
Priority to JP2022067716A priority patent/JP7571078B2/ja
Ceased legal-status Critical Current

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    • A61K9/0043—Nose
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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Definitions

  • nasal pharmaceutical compositions comprising a porous excipient and an active agent, wherein the active agent is loaded onto a surface of the porous excipient located inside pores of the porous excipient, and wherein the composition is adapted for nasal administration. Also described herein are methods of making and using nasal pharmaceutical compositions.
  • Intranasal delivery of active agents is limited due to the physiological characteristics of the nasal cavity, the physicochemical properties of the active agents, and pharmaceutical factors such as the limited application volumes.
  • the dose solubility volume which considers the solubility of an active agent in view of its dose, is especially poor in compositions with active agents that are poorly soluble or unstable active in physiological solutions.
  • additional additives such as a suspending agent, cosolvents, charge modifying agents, degradative enzyme inhibitors, antioxidants, stabilizers, membrane -penetration enhancing agents, emulsifying agents, wetting agents, adhesives, viscosity enhancing agents, and/or taste-masking agents further increases the volume of such compositions.
  • Such high volumes are problematic, especially in the context of nasal delivery compositions.
  • nasal pharmaceutical compositions comprising a porous excipient and an active agent, wherein the active agent is loaded onto a surface of the porous excipient located inside pores of the porous excipient, and wherein the composition is adapted for nasal administration.
  • the porous excipient comprises a material selected from the group consisting of inorganic porous materials, organic-inorganic hybrids, organic polymers, and complexing agents.
  • the porous excipient is an inorganic porous material selected from the group consisting of microporous silica, mesoporous silica, macroporous silica, polyorganosiloxanes, pharmaceutical clays, silicon dioxide nanotubes, silica gel, magnesium alumosilicate, anhydrous calcium phosphate, and calcium carbonate.
  • the porous excipient is colloidal silicon dioxide.
  • the porous excipient is an organic-inorganic hybrid that is a metal-organic framework.
  • the porous excipient is an organic polymer formed by a carbon-carbon coupling reaction, wherein the organic-inorganic hybrid comprises non-metallic elements.
  • the porous excipient is a complexing agent is an ion exchange resin selected from the group consisting of ⁇ -cyclodextrin-based porous silica, a- cyclodextrin-based porous silica, hydroxpropyl-P-cyclodextrin-based porous silica, and porous materials based on other ion exchange resins.
  • the porous excipient comprises pores with a longest diameter in any dimension of up to 2 nm.
  • the porous excipient loaded with the active agent is coated with a polymer.
  • the polymer is selected from the group consisting of a linear polymer, a cellulose-containing polymer, a copolymer, a cross-linked polymer, a collagen- containing polymer, and combinations of any two or more thereof.
  • the linear polymer is selected from the group consisting of polyvinylpyrrolidone, hyaluronic acid, chitosan, xanthan, alginate, polyvinyl acetate, sodium starch glycolate, and combinations of any two or more thereof.
  • the cellulose-containing polymer is sodium carboxymethylcellulose.
  • the copolymer is selected from the group consisting of polyvinylpyrrolidone/polyvinyl acetate, polyvinylpyrrolidone/polyvinyl alcohol, polyvinyl alcohol/PEG, polyvinyl caprolactam/polyvinyl acetate/polyethylene glycol, and combinations of any two or more thereof.
  • the cross-linked polymer is selected from the group consisting of cross-linked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, and combinations of any two or more thereof.
  • the collagen-containing polymer is gelatin.
  • pores in the porous excipient loaded with the active agent are capped with a coating.
  • the composition comprises an active agent selected from the group consisting of aripiprazol, quetiapin, paliperidon, duloxetine, dopamine, testosterone, glatirameracetat, interferon beta- la, interferon beta- lb, fingolimod, natalizumab,
  • an active agent selected from the group consisting of aripiprazol, quetiapin, paliperidon, duloxetine, dopamine, testosterone, glatirameracetat, interferon beta- la, interferon beta- lb, fingolimod, natalizumab,
  • dimethylfumarat pregnenolone, memantine, rivastigmin, donepezil, desvenlafaxine, progesterone, eszopiclone, eszopiclone, atomoxetin, guanfacine, methylphenidate,
  • the composition is a vaccine, and the active agent comprises an immunogen.
  • the active agent is in amorphous form.
  • the composition comprises a therapeutically effective amount of the active agent. In some embodiments, the composition comprises from about 1% to about 50% (w/w) active agent based on the weight of the composition.
  • the composition is in the form of a gel.
  • the loaded porous excipient is dispersed in a gel.
  • the gel comprises a vehicle comprising an oil or mixture of oils.
  • the vehicle comprises castor oil.
  • Some embodiments comprise nasal pharmaceutical compositions comprising: (a) a porous excipient and an active agent, wherein the active agent is loaded onto a surface of the porous excipient located inside pores of the porous excipient; (b) a lipophilic or partly lipophilic vehicle; and (c) a viscosity-regulating agent.
  • Some embodiments comprise nasal pharmaceutical compositions comprising: (a) a porous excipient and an active agent, wherein the active agent is loaded onto a surface of the porous excipient located inside pores of the porous excipient; (b) a shell disposed on the porous excipient, wherein the shell contains an active agent that is the same as or different from the active agent loaded onto the porous excipient; (c) a lipophilic or partly lipophilic vehicle; (d) a viscosity-regulating agent; and (e) a surfactant.
  • the lipophilic or partly lipophilic vehicle contains an active agent.
  • Some embodiments comprise nasal pharmaceutical compositions comprising: (a) a mesoporous silica excipient and an active agent, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (b) at least one lipophilic or partly lipophilic vehicle; and (c) at least one viscosity-regulating agent.
  • Some embodiments comprise nasal pharmaceutical compositions comprising: (a) from about 0.5% to about 50% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) from about 0.5% to about 40% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (b) from about 50% to about 90% w/w of castor oil, based on the weight of the composition; and (c) from about 2% to about 6% w/w of a mixture of oleoyl macrogolglycerides, based on the weight of the composition.
  • Some embodiments comprise nasal pharmaceutical compositions comprising: (a) about 8% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) about 5% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (c) about 80% w/w of castor oil, based on the weight of the composition; and (d) about 10% w/w of colloidal silicon dioxide, based on the weight of the composition.
  • Some embodiments comprise nasal pharmaceutical compositions comprising: (a) about 8% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) about 5% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (c) about 80% w/w of castor oil, based on the weight of the composition; and (d) about 4% w/w of a mixture of oleoyl macrogolglycerides, based on the weight of the composition.
  • the active agent is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the active agent is progesterone.
  • Some embodiments comprise methods for intranasal delivery of an active agent, comprising nasally administering to a subject in need thereof a composition as described herein.
  • the active agent comprises an immunogen, such as wherein: (a) the condition is influenza, and the active agent is live attenuated influenza virus, inactivated vims, or viral antigens; the condition is hepatitis B, and the active agent is Hepatitis B virus (HBV), surface hepatitis B antigens (HBsAg), and/or core hepatitis B antigens (HBcAg); or (c)
  • the condition is meningitis, and the active agent is meningococcal polysaccharide vaccine (MPSV4, polysaccharide from the surface of the meningococcal bacteria), meningococcal conjugate vaccine (MCV4, polysaccharide chemically bonded to protein) and/or meningococcal serogroup B vaccine (MenB, which contains four proteins taken from group B Neisseria mening
  • A/Switzerland/9715293/2013 H3N2
  • H3N2 A/Switzerland/9715293/2013
  • B/Phuket/3073/2013 B/Phuket/3073/2013-like strain (B/Yamagata lineage)
  • the antigens are selected from the group consisting of antigens from influenza virus A/Panama 2007/99 (H3N2),
  • compositions for use in vaccinating against a condition wherein the active agent comprises an immunogen such as wherein: (a) the condition is influenza, and the active agent is live attenuated influenza vims, inactivated virus, or viral antigens; (b) The condition is hepatitis B, and the active agent is Hepatitis B virus (HBV), surface hepatitis B antigens (HBsAg), and/or core hepatitis B antigens (HBcAg); or (c) The condition is meningitis, and the active agent is meningococcal polysaccharide vaccine (MPSV4, polysaccharide from the surface of the meningococcal bacteria), meningococcal conjugate vaccine (MCV4, polysaccharide chemically bonded to protein) and/or meningococcal serogroup B vaccine (MenB, which contains four proteins taken from group B Neisseria meningitidis bacteria).
  • MPSV4 meningococcal polysacchari
  • compositions for use in making a vaccine against a condition wherein the active agent comprises an immunogen, such as wherein: (a) the condition is influenza, and the active agent is live attenuated influenza virus, inactivated virus, or viral antigens; (b) The condition is hepatitis B, and the active agent is Hepatitis B virus (HBV), surface hepatitis B antigens (HBsAg), and/or core hepatitis B antigens (HBcAg); or (c) The condition is meningitis, and the active agent is meningococcal polysaccharide vaccine
  • MSV meningococcal conjugate vaccine
  • meningococcal serogroup B vaccine (MenB, which contains four proteins taken from group B Neisseria meningitidis bacteria).
  • Also provided are methods for treating a condition comprising nasally administering a composition as described herein to a subject in need thereof, wherein: (a) the condition is hypogonadism, female sexual dysfunction, female arousal disorder, anorgasmia, or hypoactive sexual desire disorder, and the active agent is testosterone; (b) the condition is a brain injury, and the active agent is progesterone; (c) the condition is schizophrenia, and the active agent is aripiprazol, auetiapin, or paliperidon; (d) the condition is anxiety, and the active agent is duloxetine or dopamine; (e) the condition is multiple sclerosis, and the active agent is testosterone, glatirameracetat, interferon beta- la, interferon beta- lb, fingolimod, natahzumab, or dimethylfumarat; (f) the condition is Alzheimer's disease, and the active agent is pregnenolone, memantine, rivas
  • compositions for use in treating a condition wherein: (a) the condition is hypogonadism, female sexual dysfunction, female arousal disorder, anorgasmia, or hypoactive sexual desire disorder, and the active agent is testosterone; (b) the condition is a brain injury, and the active agent is progesterone; (c) the condition is schizophrenia, and the active agent is aripiprazol, auetiapin, or paliperidon; (d) the condition is anxiety, and the active agent is duloxetine or dopamine; (e) the condition is multiple sclerosis, and the active agent is testosterone, glatirameracetat, interferon beta- la, interferon beta- lb, fingolimod, natalizumab, or dimethylfumarat; (f) the condition is Alzheimer's disease, and the active agent is pregnenolone, memantine, rivastigmin, or donepezil; (g) the condition is depression, and the
  • compositions for use in making a medicament for the treatment of a condition wherein: (a) the condition is hypogonadism, female sexual dysfunction, female arousal disorder, anorgasmia, or hypoactive sexual desire disorder, and the active agent is testosterone; (b) the condition is a brain injury, and the active agent is progesterone; (c) the condition is schizophrenia, and the active agent is aripiprazol, auetiapin, or paliperidon; (d) the condition is anxiety, and the active agent is duloxetine or dopamine; (e) the condition is multiple sclerosis, and the active agent is testosterone, glatirameracetat, interferon beta- la, interferon beta- lb, fingolimod, natalizumab, or dimethylfumarat; (f) the condition is
  • Alzheimer's disease and the active agent is pregnenolone, memantine, rivastigmin, or donepezil;
  • the condition is depression, and the active agent is desvenlafaxine, duloxetine, or dopamine;
  • the condition is insomnia, and the active agent is progesterone, eszopiclone or eszopiclone;
  • the condition is attention deficit hyperactive disoder, and the active agent is tomoxetin, guanfacine, methylphenidate, lisdexamfetamine, or dopamine;
  • the condition is traumatic brain injury, and the active agent progesterone or recombinant tissue plasminogen activator (rt-PA);
  • the condition is a braun tumor, and the active agent is methotrexate, raititrexed, 5-fluorouracil, telomerase inhibitor, or monoclonal antibodies;
  • the condition is epilepsy, and the active agent is mid
  • Some embodiments comprise methods for treating nasal congestion comprising administering a composition to a subject in need thereof, wherein the active agent comprises one or more of a nasal antihistamine and a decongestant.
  • the nasal congestion is caused by one or more of dry nose/crusts, common cold, hay fever, upper respiratory tract allergies, and age.
  • the active agent comprises one or more of a corticosteroid, naphazoline, oxymetazoline, adrenaline, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoin, and plant and/or anthroposophical substances.
  • Some embodiments comprise a composition for use in treating nasal congestion.
  • Some embodiments comprise a composition for use in making a medicament for tretament of nasal congestion.
  • the nasal congestion is caused by one or more of dry nose/crusts, common cold, hay fever, upper respiratory tract allergies, and age.
  • the active agent comprises one or more of a corticosteroid, naphazoline, oxymetazoline, adrenaline, phenylephrine, nasal saline spray, brompheniramine,
  • chlorpheniramine clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoin, and plant and/or anthroposophical substances.
  • Figure 1 shows scanning electron micrographs of various spray dried compositions as described herein with progesterone and SYLOID® 72FP particles.
  • Figure 2 shows scanning electron micrographs of various spray dried compositions as described herein with progesterone and SYLOID® 244FP particles.
  • Figure 3 shows scanning electron micrographs of spray dried compositions as described herein with SYLOID® 72FP particles and 244FP particles.
  • Figure 4 shows scanning electron micrographs of spray dried progesterone.
  • Figure 5 shows differential scanning calorimetry measurements of spray-dried progesterone, spray-dried SYLOID® 72FP, and spray-dried SYLOID® 244FP.
  • Figure 6 shows differential scanning calorimetry measurements of spray-dried compositions as described herein with progesterone and SYLOID® 244FP.
  • Figure 7 shows differential scanning calorimetry measurements of spray-dried compositions as described herein with progesterone and SYLOID® 72FP.
  • Figure 8 shows differential scanning calorimetry thermograms of compositions as described herein with progesterone loaded onto ordered mesoporous silica OSM-7.
  • Figure 9 shows differential scanning calorimetry thermograms of compositions as described herein with 20% and 40% progesterone loaded onto ordered mesoporous silica OSM- 7.
  • Figure 10 shows the pore size distribution of OSM-7 particles with and without progesterone absorbed to the OSM-7.
  • Figure 11 shows differential scanning calorimetry thermograms of compositions as described herein with testosterone loaded onto ordered mesoporous silica OSM-7.
  • Figure 12 shows differential scanning calorimetry thermograms of compositions as described herein with 20% and 40% testosterone loaded onto ordered mesoporous silica OSM- 7.
  • Figure 13 shows the pore size distribution of OSM-7 particles with and without testosterone absorbed to the OSM-7.
  • Figure 14 shows scanning electron micrographs of spray dried testosterone.
  • Figure 15 shows scanning electron micrographs of spray dried compositions as described herein with testosterone and polylactide.
  • Figure 16 shows scanning electron micrographs of spray dried compositions as described herein with testosterone and chitosan.
  • Figure 17 shows scanning electron micrographs of spray dried compositions as described herein with testosterone and gelatin.
  • Figure 18 shows scanning electron micrographs of spray dried compositions as described herein with testosterone, gelatin, and an emulsifying agent.
  • Figure 19 shows scanning electron micrographs of gelatin particles sprayed in ethanol/water mixtures with various ethanohwater ratios.
  • Figure 20 shows scanning electron micrographs of spray dried mesoporous silica particles.
  • Figure 21 shows scanning electron micrographs of spray dried mesoporous silica particles, some of which are loaded with testosterone as described herein.
  • Figure 22 shows scanning electron micrographs of compositions as described herein with testosterone and SYLOID® 244FP.
  • Figure 23 shows scanning electron micrographs of compositions as described herein with testosterone and AEROSIL® 200.
  • Figure 24 sets forth pictures of various compositions as described herein with testosterone and mesoporous silica particles, and demonstrates textures associated with the various compositions.
  • Figure 25 sets forth pictures of various compositions as described herein with testosterone and mesoporous silica particles, and demonstrates textures associated with the various compositions.
  • Figure 26 shows scanning electron micrographs of mesoporous silica particles, some of which are loaded with testosterone, that were spray dried with a two-fluid nozzle.
  • Figure 27 shows scanning electron micrographs of mesoporous silica particles, some of which are loaded with testosterone, that were spray dried with a three-fluid nozzle.
  • Figure 28 sets forth photographs demonstrating a rod test conducted to assess flow behavior of various compositions.
  • Figure 29 shows solubility data associated with various testosterone compositions as described herein where the quantity of castor oil in the composition is held constant.
  • Figure 30 shows solubility data associated with various testosterone compositions as described herein where the quantity of castor oil in the composition is varied.
  • Figure 31 shows differential scanning calorimetry measurements obtained with two different batches of testosterone.
  • Figure 32 shows differential scanning calorimetry measurements obtained on two different batches of testosterone spray dried in ethanol.
  • Figure 33 shows differential scanning calorimetry measurements obtained with various compositions with polylactic acid.
  • Figure 34 shows differential scanning calorimetry measurements obtained with various compositions with gelatin.
  • Figure 35 shows differential scanning calorimetry measurements obtained with compositions having SYLOID® 244FP particles.
  • Figure 36 shows differential scanning calorimetry measurements obtained with compositions having SYLOID® 244FP particles provided with a gelatin shell.
  • Figure 37 shows differential scanning calorimetry measurements obtained with compositions having AEROSIL® 200 particles.
  • Figure 38 shows differential scanning calorimetry measurements obtained with compositions having SYLOID® XDP6035 particles.
  • subject denotes any mammal in need of active agent therapy, including humans.
  • a subject may be suffering from or at risk of developing a condition that can be treated or prevented with an active agent, or may be taking an active agent for health maintenance purposes.
  • the phrases "therapeutically effective amount” and “therapeutic level” mean that active agent dosage or plasma concentration in a subject, respectively, that provides the specific pharmacological effect for which the active agent is administered in a subject in need of such treatment. It is emphasized that a therapeutically effective amount or therapeutic level of an active agent will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art. For convenience only, exemplary dosages, active agent delivery amounts, therapeutically effective amounts and therapeutic levels are provided below with reference to adult human subjects. Those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or
  • Theoretical loading of an active agent means the wt% of the of the active agent in a composition or porous excipient if the active agent is incorporated into the composition or porous excipient with 100% efficiency.
  • theoretical loading 100 x (weight of active agent added (g)) / (weight of active agent (g) + porous excipient (g)).
  • “Actual loading” of an active agent means the actual amount of active agent incorporated into the composition or porous excipient.
  • the actual loading of an active agent on a porous excipient can be calculated using the following equation: 100 x (weight of active agent (g) in 1 gram of loaded porous excipient) / (1 g of loaded porous excipient).
  • Loading efficiency 100 x (total amount of active agent in the yield (g)) / (actual amount of active agent added during loading).
  • the active agent can include any one or more therapeutic agents that can be administered intranasally for a therapeutic effect.
  • the active agent comprises a hormone, such as testosterone, progesterone, pregnenolone, or a prodrug or derivative of any of these.
  • the active agent comprises a
  • the active agent comprises an opioid analgesic, such as fentanyl or hydromorphone.
  • the active agent comprises a benzodiazepine, such as midazolam.
  • the active agent comprises a protein, such as insulin or a growth hormone (e.g., human growth hormone).
  • the active agent comprises a cholinesterase inhibitor, such as donepezil, rivastigmine, or galantamine.
  • the active agent comprises a nasal antihistamine and/or a decongestant, such as a corticosteroid, naphazoline, oxymetazoline, adrenaline, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoin, or plants and anthroposophical substances.
  • a nasal antihistamine and/or a decongestant such as a corticosteroid, naphazoline, oxymetazoline, adrenaline, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoin, or plants and anthroposophical substances.
  • the active agent is selected from the group consisting of aripiprazol, quetiapin, paliperidon, duloxetine, dopamine, testosterone, glatirameraeetat, interferon beta-la, interferon beta-lb, fingolimod, natalizumab, dimethylfumarat, pregnenolone, memantine, rivastigmin, donepezil,
  • desvenlafaxine desvenlafaxine, progesterone, eszopiclone, eszopiclone, atomoxetin, guanfacine, methylphenidate, lisdexarrifetamine, recombinant tissue plasminogen activator (rt-PA), methotrexate, raltitrexed, 5-fluorouracil, telomerase inhibitor, monoclonal antibodies, midazolam, lacosamide, levetiracetam, lamotrigine, valproic acid, oxycodone, pregabalin, buprenorphine, hydrocodone, fentanyl, safinamide, ropinirole, pramipexole, L-DOPA, selegiline, cabergoline, istradefylline, and combinations of two or more thereof.
  • rt-PA tissue plasminogen activator
  • the composition is useful as a vaccine, and the active agent comprises an immunogen, such as an influenza vaccine, a hepatitis B vaccine, or a meningitis vaccine.
  • the active agent loaded onto the porous excipient can be imnmunogenic against influenza.
  • Exemplary active agents loaded onto the porous excipient when the composition is useful as an influenza vaccine include live attenuated influenza (such as but not limited to A/California 7/2009 (H IN 1) or an A/California 7/2009 (HlNl)-like strain; A/Switzerland/9715293/2013 (H3N2) or an A/Switzerland/9715293/2013 (H3N2)-like strain; B/Phuket/3073/2013 or a live attenuated influenza (such as but not limited to A/California 7/2009 (H IN 1) or an A/California 7/2009 (HlNl)-like strain; A/Switzerland/9715293/2013 (H3N2) or an A/Switzerland/9715293/2013 (H3N2)-like strain; B/Phuket/3073/2013 or a live attenuated influenza (such as but not limited to A/California 7
  • B/Phuket/3073/2013-like strain B/Yamagata lineage
  • the active agent loaded onto the porous excipient comprises an inactivated virus or viral antigens (such as but not limited to antigens from influenza virus A/Panama/2007/99 (H3N2), B/Guandong/2000, and/or an avian strain such as A/Duck/Singapore/97 (H5N3)).
  • an inactivated virus or viral antigens such as but not limited to antigens from influenza virus A/Panama/2007/99 (H3N2), B/Guandong/2000, and/or an avian strain such as A/Duck/Singapore/97 (H5N3)).
  • the active agent loaded onto the porous excipient can comprise, for example, Hepatitis B virus (HBV), surface hepatitis B antigens (HBsAg), and/or core hepatitis B antigens (HBcAg).
  • HBV Hepatitis B virus
  • HBsAg surface hepatitis B antigens
  • HBcAg core hepatitis B antigens
  • the active agent loaded onto the porous excipient can comprise, for example, meningococcal
  • the composition is useful in treating nasal congestion, such as may be caused by dry nose/crusts, common cold, hay fever, upper respiratory tract allergies, or age.
  • the active agent comprises a nasal antihistamine and/or a decongestant, such as a corticosteroid, naphazoline,
  • oxymetazoline adrenaline, phenylephrine, nasal saline spray, brompheniramine,
  • chlorpheniramine clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoin, or plants and anthroposophical substances.
  • the composition comprises active agent in amorphous form. In some embodiments, the composition comprises an active agent in crystalline form. In some embodiments, the composition comprises an active agent in both amorphous form and crystalline form.
  • amorphous active agent may be loaded onto the porous excipient inside the pores of the excipient, and crystalline active agent may be included in a coating and/or provided in a vehicle of the composition, such as being dissolved, suspended, or dispersed in the vehicle of the composition.
  • the composition contains an active agent that is less than about 0.1%, less than about 0.5%, less than about 1%, or less than about 5% in crystalline form, such as less than 0.1%, less than 0.5%, less than 1%, or less than 5% in crystalline form. In some embodiments, the composition contains substantially no crystalline form of the active agent.
  • the active agent can be used in a form that it not typically used, such as a polymorph or salt that may not exhibit satisfactory stability in typical formulations. Without being bound by theory, it is believed that loading the active agent onto a porous excipient as described herein may stabilize the active agent, both against chemical reactions and against physical modifications (such as intro-polymorph conversion). In some
  • the porous excipient is selected and/or prepared for this purpose, such as by using a certain quality of silicon dioxide that stabilizes the active agent at issue.
  • Nasal Compositions comprising a porous excipient and an active agent. Also provided are methods of making and using nasal compositions comprising a porous excipient and an active agent.
  • nasal compositions compositions suitable for, or adapted for, nasal delivery, including intra-nasal delivery.
  • the specific form of the nasal composition is not limited.
  • the nasal composition is in the form of a solution, suspension, dispersion, emulsion, or gel.
  • the composition is in the form of an oily liquid.
  • the composition is non-aqueous or water-free. (As used herein, “water-free” means that the composition is formulated without water, although trace amounts may be present.)
  • the composition comprises a water-free semi-liquid phase.
  • the composition is a hydrophilic gel or an emulgel (i.e., an emulsion incorporated in a gel base).
  • the composition is a hydrophobic gel, such as an oleogel or an organogel.
  • the composition comprises a three-dimensional, viscoelastic gel with small molecular weight organoregulators and/or polymeric gelators. In some embodiments, the composition is spreadable.
  • the nasal compositions described herein comprise (a) an active agent and (b) a porous excipient, wherein the active agent is loaded onto a surface of the porous excipient located inside pores of the porous excipient.
  • the compositions further comprise a vehicle.
  • the compositions further comprise a viscosity-regulating agent.
  • the porous excipient is provided with a shell, which may (or may not) contain an active agent (which can be the same as or different from the active agent loaded onto the porous excipient).
  • the composition comprises a surfactant.
  • the composition comprises porous excipient embedded in a gel network, such as a hydrophobic gel.
  • At least a portion of the porous excipient loaded with active agent is in the form of particles.
  • about 10% of particles have a longest diameter in any dimension of less than about 0.2 ⁇ , or less than about 0.1 ⁇ .
  • about 90% of the particles have a longest diameter of less than about 15.5 ⁇ , less than about 7.5 ⁇ , or less than about 4.2 ⁇ .
  • about 50% of the particles have a longest diameter of less than about 5.2 ⁇ , less than about 2 ⁇ , or less than about 0.9 ⁇ .
  • the active agent is present in the nasal composition in an amount of from about 0.1% w/w to about 70% w/w, including from about 0.5% w/w to about 40% w/w, about 5% w/w to about 40% w/w, about 10% w/w to about 30% w/w, and about 15% w/w to about 25% w/w, based on the total weight of the composition, and amounts between any of these values, including about 0.1%, about 0.5%, about 1% w/w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w or about 70% w/w.
  • the active agent is present in the nasal composition in an amount of from 0.1% w/w to 70% w/w, including from 0.5% w/w to 40% w/w, 5% w/w to 40% w/w, 10% w/w to 30% w/w, and 15% w/w to 25% w/w, based on the total weight of the composition.
  • the active agent is present in an amount of 0.1%, 0.5%, 1% w/w, 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w or 70% w/w, based on the total weight of the composition.
  • the composition comprises at least about 1 ⁇ g of active agent per 150 mg of the composition. In some embodiments, the composition comprises from about 1 ⁇ g to about 100 mg of active agent per 150 mg of the composition, or about 1 mg to about 50 mg of active agent per 150 mg of the composition, or about 5 mg to about 20 mg of active agent per 150 mg of the composition, or about 50 ⁇ g to about 250 ⁇ g of active agent per 150 mg of the composition.
  • the composition comprises about 1 ⁇ g, about 10 ⁇ g, about 20 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 250 ⁇ g, about 500 ⁇ g, about 1 mg, about 2 mg, about 5 mg, about 5.5 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 50 mg of active agent per 150 mg of the composition.
  • the composition comprises 1 ⁇ g, 10 ⁇ g, 20 ⁇ g, 50 ⁇ g, 100 ⁇ g, 250 ⁇ g, 500 ⁇ g 1 mg, 2 mg, 5 mg, 5.5 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg of active agent per 150 mg of the composition.
  • the composition may be adapted for nasal administration of any suitable amount of composition, keeping in mind the volume limitations of nasal administration.
  • the composition is adapted for administration of about 0.1 ml to about 1 ml per nostril, such as from about 0.1 ml to about 0.3 ml, about 0.15 ml to about 0.25 ml, or about 0.175 to about 0.225 ml per nostril.
  • Some embodiments are adapted for administration of 0.1 ml to 1 ml per nostril, such as from 0.1 ml to 0.3 ml, 0.15 ml to 0.25 ml, or 0.175 to 0.225 ml per nostril
  • the composition is adapted for administration of about 0.1 ml, about 0.15 ml, about 0.2 ml, about 0. 25 ml, or about 0.3 ml per nostril.
  • embodiments are adapted for administration of 0.1 ml, 0.15 ml, 0.2 ml, 0. 25 ml, or 0.3 ml per nostril. In some embodiments, the composition is adapted for administration of about 0.2 ml or less per nostril. In some embodiments, the composition is adapted for administration of 0.2 ml or less per nostril.
  • the composition is adapted for once daily administration per nostril, to one or both nostrils. In some embodiments, the composition is adapted for twice daily administration per nostril, to one or both nostrils. In some embodiments, the composition is administered three, four, five, or six times per day per nostril, to one or both nostrils.
  • the composition is stable (e.g., contains substantially no degradation-related impurities) for at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months, such as after storage, for example., at 25 °C and 60% relative humidity, at 30°C and 65% relative humidity, or room temperature and humidity conditions.
  • the composition is stable for at least 1 month, at least 2 months, at least 3 months, or at least 6 months, such as after storage, for example, at 25°C and 60% relative humidity, at 30°C and 65% relative humidity, or room temperature and humidity conditions.
  • the nasal compositions described herein comprise (a) an active agent and (b) a porous excipient.
  • the porous excipient can be any porous material onto which the active agent can be loaded.
  • the active agent is loaded onto surfaces of the porous excipient, including surfaces located inside pores of the excipient.
  • the porous excipient acts as a matrix for the active agent.
  • the composition further comprises active agent that is not loaded onto the porous excipient; for example, the composition can comprise active agent in addition to active agent that is loaded onto the porous excipient.
  • the porous excipient may be comprised of any material suitable for use in a nasal pharmaceutical composition and onto which active agent can be loaded in accordance with the disclosure herein.
  • suitable materials are provided below.
  • the porous agent comprises an inorganic porous material, such as colloidal silicon dioxide, micro-porous silicon dioxide, meso-porous silicon dioxide, macro- porous silicon dioxide, polyorganosiloxanes, pharmaceutical clays, silicon dioxide nanotubes, silicon dioxide gel, magnesium alumosilicate (such as but not limited to VEEGUM® from Vanderbilt Minerals, LLC), activated carbon, anhydrous calcium phosphate, calcium carbonate, alumina, and combinations of any two or more thereof.
  • exemplary inorganic porous materials include porous silicon dioxide commercially available under the SYLOID® brand from W.R. Grace & Co.
  • porous silicon dioxide available under the AEROPERL® brand from Evonik
  • the porous agent comprises silicon-based powders, which may be hydrophobic or hydrophilic, e.g., depending on groups chemically bonded to their surfaces.
  • the porous excipient comprises an organic-inorganic hybrid, such as metal-organic frameworks (MOFs).
  • MOFs metal-organic frameworks
  • Exemplary hybrid materials can be formed by self- assembly of polydentate bridging ligands and metal connecting points.
  • the porous excipient comprises organic polymers, such as microporous organic polymers, polystyrene, cellulose, and/or poly(methyl methacrylate).
  • microporous organic polymers are formed by carbon-carbon coupling reactions and comprised of non-metallic elements such as carbon, hydrogen, oxygen, nitrogen, and/or boron.
  • organic polymers are produced by emulsion
  • networks of organic polymers are constructed from small organic building blocks.
  • the porous excipient comprises porous materials based on complexing agents, such as an ion exchange resin (such as but not limited to cross-linked polystyrene) or an adsorbent (such as but not limited to ⁇ -cyclodextrin-based porous silica, a-cyclodextrin -based porous silica, hydroxpropyl-P-cyclodextrin -based porous silica, and porous materials based on other adsorbent resins).
  • complexing agents such as an ion exchange resin (such as but not limited to cross-linked polystyrene) or an adsorbent (such as but not limited to ⁇ -cyclodextrin-based porous silica, a-cyclodextrin -based porous silica, hydroxpropyl-P-cyclodextrin -based porous silica, and porous materials based on other adsorbent resins).
  • the porous excipient comprises a material with pores with highly variable sizes and irregular shapes, such as an agent comprising polylactide and/or polylactic acid.
  • the polylactide comprises polylactides available under the RESOMER® brand available from Sigma- Aldrich (such as but not limited to RESOMER® 202H (which has a molecular weight of about 10,000 to about 18,000 Da; a viscosity of about 0.16 to about 0.24 dl/g; a T g of about 44 to about 48°C; and free carboxylic acid end groups) and RESOMER® 202S (which has a molecular weight of about 10,000 to about 18,000 Da; a viscosity of about 0.16 to about 0.24 dl/g; a T g of about 38 to about 42°C; and ester terminated end groups)), and combinations of two or more thereof.
  • RESOMER® 202H which has a molecular weight of about 10,000 to about 18,000 Da; a viscosity of about 0.16 to about
  • the porous agent comprises polysaccharides, such as chitosan (such as but not limited to chitosan with 95% degree of deacylation and a viscosity of about 200 mPa).
  • chitosan such as but not limited to chitosan with 95% degree of deacylation and a viscosity of about 200 mPa.
  • An exemplary chitosan in this regard is CHITOSCIENCE® Chitosan 95/200 from Heppe Medical Chitosan GmbH.
  • the porous agent comprises peptides and/or proteins, such as gelatin (such as but not limited to gelatin with bloom grades F15, F20, F25, or combinations of two or more thereof).
  • the porous excipient comprises porous particles. Without being bound by theory, it is believed that even small and large particles can be effective by fixing them in a gel network using chemical and/or physical bonds, such as H-bonding and van der Walls forces.
  • the particles may have a longest diameter in any dimension of from about 0.5 ⁇ to about 350 ⁇ , such as from about 50 ⁇ to about 300 ⁇ , about 100 ⁇ to about 250 ⁇ , about 150 ⁇ to about 200 ⁇ , or about 3 ⁇ to about 35 ⁇ .
  • the longest diameter is from 0.5 ⁇ to 350 ⁇ , such as from 50 ⁇ to 300 ⁇ , 100 ⁇ to 250 ⁇ , 150 ⁇ to 200 ⁇ , or 3 ⁇ to 35 ⁇ .
  • the particles have a longest diameter of about 0.5 ⁇ , about 0.8 ⁇ , about 1 ⁇ , about 2 ⁇ , about 3 ⁇ , about 5 ⁇ , about 10 ⁇ , about 35 ⁇ , about 60 ⁇ , or about 150 ⁇ .
  • the particles have a longest diameter of 0.5 ⁇ , 0.8 ⁇ , 1 ⁇ , 2 ⁇ , 3 ⁇ , 5 ⁇ , 10 ⁇ , 35 ⁇ , 60 ⁇ , or 150 ⁇ .
  • the particles have a mean diameter of from about 0.5 ⁇ to about 350 ⁇ , such as from about 50 ⁇ to about 300 ⁇ , about 100 ⁇ to about 250 ⁇ , about 150 ⁇ to about 200 ⁇ , or about 3 ⁇ to about 35 ⁇ .
  • the mean diameter is from 0.5 ⁇ to 350 ⁇ , such as from 50 ⁇ to 300 ⁇ , 100 ⁇ to 250 ⁇ , 150 ⁇ to 200 ⁇ , or 3 ⁇ to 35 ⁇ .
  • the median diameter of the particles in a composition is about 0.5 ⁇ , about 0.8 ⁇ , about 1 ⁇ , about 2 ⁇ , about 3 ⁇ , about 5 ⁇ , about 10 ⁇ , about 35 ⁇ , about 60 ⁇ , or about 150 ⁇ . In some embodiments, the median diameter of the particles in a composition is 0.5 ⁇ , 0.8 ⁇ , 1 ⁇ , 2 ⁇ , 3 ⁇ , 5 ⁇ , 10 ⁇ , 35 ⁇ , 60 ⁇ , or 150 ⁇ .
  • the porous excipient may comprise pores with a longest diameter in any dimension of 2 nm or less (e.g., the porous excipient comprises micro- porous materials).
  • the porous excipient comprises pores with a longest diameter of from about 2 nm to about 50 nm, such as from 20 nm to 50 nm (e.g., the porous excipient comprises meso-porous materials).
  • the porous excipient comprises pores with a longest diameter of 50 nm or more (e.g. , the porous excipient comprises macro-porous materials).
  • the porous excipient comprises pores with a longest diameter of from about 2 nm to about 20 nm, such as from 2 nm to 20 nm. In some embodiments, at least about 90% of the pores have a diameter of from about 5 nm to about 6 nm, about 5 nm to about 7.5 nm, about 5.5 nm to about 7 nm, about 6 nm to about 7.5 nm, or about 6 nm to about 8 nm.
  • the pores have a diameter of from 5 nm to 6 nm, 5 nm to 7.5 nm, 5.5 nm to 7 nm, 6 nm to 7.5 nm, or 6 nm to 8 nm.
  • the pores have an average volume of from about 0.5 ml/g to about 2 ml/g, such as about 1 ml/g, about 1.6 ml/g, or about 1.75 ml/g.
  • the pores have an average volume of from 0.5 ml/g to 2 ml/g, such as 1 ml/g, 1.6 ml/g, or 1.75 ml/g.
  • the pores have an average volume of greater than about 0.9 ml/g, or greater than 0.9 ml/g.
  • the pores have a surface area of about 300
  • the pores have
  • the pores have a surface area of 1000 m /g or greater.
  • the porous excipient may have pores of any type of pore structure.
  • the pore cross-section may have a regular geometric shape, such as a circular, elliptical, rectangular, or square shape, or an irregular shape.
  • the porous excipient comprises pores with a regular shape and pores with an irregular shape.
  • the porous excipient additionally or alternatively comprises pores with a connected pore structure, pores with an unconnected pore structure, or both.
  • the porous excipient additionally or alternatively comprises ordered arrays of pores, disordered arrays of pores, or both.
  • the composition may comprise any suitable amount of porous excipient, such as any amount effective to provide a therapeutically effective dose of the active agent while still being suitable for nasal administration.
  • the composition comprises from about 0.01 to about 0.5 g of porous excipient, such as from about 0.01 g to about 0.4 g of porous excipient, about 0.1 g to about 0.25 g, or about 0.05 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, or about 0.3 g of porous excipient, where the weight corresponds to the amount porous excipient prior to loading it with active agent.
  • the composition comprises from 0.01 to 0.5 g of porous excipient, such as from 0.01 g to 0.4 g of porous excipient, 0.1 g to 0.25 g, or 0.05 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, or 0.3 g of porous excipient. In some embodiments, the composition comprises from about 0.5% to about 30% w/w, about 1% to about 20% w/w, about 5% to about 15% w/w, or about 8% to about 10% w/w porous excipient, based on the weight of the pre-loaded porous excipient and the total weight of the composition.
  • the composition comprises from 0.5% to 30% w/w, 1% to 20% w/w, 5% to 15% w/w, or 8% to 10% w/w porous excipient, based on the weight of the pre-loaded porous excipient and the total weight of the composition.
  • the active agent is loaded onto the porous excipient in an amount of from about 1% w/w to about 70% w/w, including from about 5% w/w to about 40% w/w, about 10% w/w to about 30% w/w, and about 15% w/w to about 25% w/w, based on the total weight of the loaded porous excipient, and amounts between any of these values, including 1% w/w, 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w or 70% w/w.
  • the weight ratio of porous excipient to active agent is from about 1: 1 to about 10: 1, such as about 1: 1 to about 5: 1. In some embodiments, the weight ratio of porous excipient to active agent is from 1 : 1 to 10: 1, such as 1 : 1 to 5: 1. In some embodiments,
  • the weight ratio of porous excipient to active agent is about 1 : 1, about 2: 1, about 3: 1, about 4: 1, or about 5: 1. In some embodiments, the weight ratio of porous excipient to active agent is 1: 1, 2: 1, 3: 1, 4: 1, or 5: 1.
  • the porous excipient may be selected and/or prepared to modify the release properties of the active agent from the composition, e.g., the porous excipient may be selected and/or prepared to exhibit active agent release-modifying properties.
  • the porous excipient may be selected and/or prepared to provide delayed release of the active agent, and/or to control release of the active agent, such as to provide release of the active agent at a predetermined rate and/or to maintain a constant therapeutic level of active agent for a specified period of time, or to provide any other type of controlled release.
  • the porous excipient allows control over active agent release (even a bi-phasic release is feasible), e.g., by change in pore size and shape of the excipient and/or by
  • the surface of the porous excipient— including the inner pore surface— can be functionalized to bind active agent and/or control release of the active agent after a certain amount of time or in response to a stimulus.
  • a hormone e.g., testosterone
  • a porous excipient can be a ligand for site-specific delivery of agents to androgen-receptor (AR) positive sites, such as AR-positive tumors or other organs like the prostate, brain, or testis.
  • the porous excipient can be functionalized to promote cellular uptake through endocytosis.
  • active agent is released from the porous excipient after cellular uptake of the porous excipient.
  • the porous excipient is functionalized with one or more organic moieties.
  • the porous excipient is functionalized with amine groups, quaternary alkyl amines, alkyl chains, alkoxysilanes, fluoenylmethoxycarbonyl- modified organosilanes, hydrophobic groups, mercaptopropyl groups, aminopropyl groups, hydroxypropyl groups, phenyl groups, or combinations of two or more thereof.
  • the porous excipient may serve one or more functions in the context of the compositions described herein.
  • the porous excipient may serve as a carrier for the active agent, may protect the active agent, and/or may delay and/or control release of the active agent. Additionally or alternatively, the porous excipient may impact the chemical, physical, physico-chemical, and/or pharmacokinetic properties of the composition, as discussed in more detail below.
  • the porous excipient acts as a protecting agent, i.e., it protects the active agent from oxidation and/or degradation and/or reaction with other components of the composition and/or environment. This can be particularly advantageous for active agents prone to oxidation and/or degradation, such as dopamine.
  • the porous excipient impacts the chemical, physical, physico-chemical and/or pharmacokinetic properties of the composition, such as by acting as a gelling agent, a structure-giving agent, a solubilizing agent (e.g., a solubility enhancer), a release-modifying agent, and/or a binding site of an active agent.
  • a solubilizing agent e.g., a solubility enhancer
  • a release-modifying agent e.g., a binding site of an active agent.
  • the active agent is loaded onto the porous excipient in a stable amorphous state, such that a supersaturated aqueous solution can be provided at an application site, which can give rise to enhanced transepithelial or transmucosal transport.
  • the number of hydroxyl groups on the porous excipient available to form inter- and intramolecular hydrogen bonding in compositions as claimed enhance dissolution.
  • the porous excipient comprises porous particles (such as but not limited to ordered mesoporous silica, or SYLOID® particles such as AL-1FP, 244FP, XDP3050, 72FP, XDP6035, or XDP3150) that can be loaded with an active agent.
  • porous particles such as but not limited to ordered mesoporous silica, or SYLOID® particles such as AL-1FP, 244FP, XDP3050, 72FP, XDP6035, or XDP3150
  • Some embodiments comprises spray dried particles with active agent loaded onto porous excipient particles.
  • the loaded particles are in a dry powder form.
  • the particles are in a granulated form.
  • the composition as a whole may be formulated to provide a desired release profile, e.g., a desired delayed and/or controlled release profile.
  • release of the active agent from the composition can be modified by varying one or more of the amount of active agent-loaded porous excipient in the composition, the amount of active agent present in any coating, the amount of active agent present in the vehicle of the composition, and/or by including one or more release-modifying agents in composition.
  • the compositions have one or more of the following advantages as compared to compositions without an active agent loaded onto a porous excipient: a reduction of the amount of solidifying excipients; improved bioavailability; low or no toxicity potential; rapid onset of action; suitability for relatively high active agent payloads; potential for sustained-release depot; more control over active agent release (even a bi-phasic release is feasible), e.g., by change in pore size and shape of the excipient and by
  • the composition is suitable for allergic patients, e.g., because the composition can lack excipients that induce an allergic response; a simple and economical manufacturing process; protection of active agents sensitive to oxygen or humidity; stabilization of the amorphous form of active ingredient; no re-crystallization of the active ingredients; an option to provide fast release of the active ingredient; ability to target systemic circulation and/or the brain and/or the spinal cord by functionalization of the excipient; the composition can be spreadable (and thus remove concerns related to propelling the active agent into a specific site of the nasal cavity and to head position, spray angle, and plume geometry); and maximal nasal mucosal surface can be covered.
  • the porous excipient comprises a coating.
  • the coating is porous, while in other embodiments the coating is nonporous.
  • the coating surrounds the porous excipient onto which active agent is loaded (e.g., provides a shell around the loaded porous excipient).
  • the coating is in the form of a film.
  • the coating functions to cap loaded pores.
  • the coating functions to cap the pores but does not completely surround the porous excipient (e.g., the pores are capped, but a shell is not formed completely around the porous excipient).
  • the coating provides delayed release of an active agent. In some embodiments, the coating allows sustained release of an active agent. In some embodiments, the coating functions to improve bioavailability of the active agent. In some embodiments, the coating functions to protect the active agent loaded onto the porous excipient. In some embodiments, the coating contains an active agent (e.g., the same active agent as contained in the pores or a different one).
  • the coating may be comprised of any material suitable for use in a nasal
  • the coating comprises one or more polymers, which may be selected to provide desired characteristics to the coating (e.g., delayed release, controlled release, protection, etc.).
  • the coating comprises polymers that are soluble in oil or partially soluble in oil, while in other embodiments the coating comprises polymers that are poorly soluble in oil or insoluble in oil.
  • the coating may comprise linear polymers, such as polyvinylpyrrolidone, hyaluronic acid, xanthan, alginate, polyvinyl acetate, sodium starch glycolate, and combinations or copolymers of any two or more thereof.
  • the coating may comprise branched polymers, such as branched polyethylene glycol or acacia gum. Additionally or alternatively, the coating may comprise cellulose- containing polymers, such as sodium carboxymethylcellulose.
  • the coating may comprise copolymers, such as polyvinylpyrrolidone/polyvinyl acetate, polyvinylpyrrolidone/polyvinyl alcohol, polyvinyl alcohol/PEG, polyvinyl
  • the coating may comprise cross-linked
  • the coating may comprise a polylactide, such as polylactic acid. Any suitable polylactide can be used, such as a polylactide that comprises RESOMER® 202H, RESOMER® 202S, Lupon DEPOR®, PLENAXIS®, and combinations of any two or more thereof. Additionally or alternatively, the coating may comprise polysaccharides, such as chitosan (such as but not limited to chitosan 95/200). Additionally or alternatively, the coating may comprise peptides and/or proteins. Additionally or alternatively, the coating may comprise gelatin (such as but not limited to F15, F20, or F25). It will be understood that a coating may comprise combinations of any of two or more of the foregoing and/or chemical modifications of any of the foregoing.
  • the coating further comprises an active agent (e.g., the active agent is loaded into or onto the coating), which may be the same or different from the active agent loaded onto the porous excipient.
  • the active agent is present in the pores of the porous excipient and also is present in the coating.
  • the coating does not contain an active agent.
  • the coating can comprise materials, such as nanoparticles, covalently bound to pore entrances.
  • Exemplary nanoparticles include cadmium sulfide (CdS) nanocrystals, Fe 3 04 nanoparticles, and cyclodextrins. Without being bound by theory, it is believed that capping loaded pores can inhibit or control release of active agent from the pores.
  • the composition comprises loaded porous excipient that comprises active agent loaded onto porous excipient particles (such as but not limited to ordered mesoporous silica, or SYLOID® particles such as 244FP, XDP3050, 72FP, XDP6035, or XDP3150), where the particles are coated with material described herein (such as but not limited to gelatin).
  • coated particles with active agent loaded onto porous excipient particles are spray dried, such as to obtain a dry powder form.
  • the nasal compositions described herein may comprise, in addition to active agent and porous excipient, a vehicle and a viscosity-regulating (e.g., gelling) agent.
  • the vehicle may be any vehicle suitable as a vehicle for a nasal pharmaceutical composition.
  • the vehicle for the porous excipient is a hydrophilic vehicle.
  • the vehicle is a lipophilic or partly lipophilic vehicle, such as a vehicle comprising one or more fats, oils, waxes, phospholipids, steroids (e.g., cholesterol), sphingolipids, ceramides, sphingosines, prostaglandins, and/or fat-oil vitamins.
  • the vehicle comprises an oil or a mixture of oils, such as vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, or peanut oil; fatty acid esters, such as ethyl- and oleyl-oleate, isopropylmyristate; medium chain triglycerides; glycerol esters of fatty acids; polyethylene glycol; phospholipids; white soft paraffin; or combinations of any two or more thereof.
  • oils such as vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, or peanut oil
  • fatty acid esters such as ethyl- and oleyl-oleate, isopropylmyristate
  • medium chain triglycerides such as ethyl- and oleyl-oleate, isopropylmyristate
  • medium chain triglycerides such as ethyl- and oleyl-oleate, isopropylmyri
  • the vehicle may be present in any suitable amount, such as an amount effective to provide desired properties for nasal administration, desired physical properties, desired release properties, desired pharmacokinetics, etc.
  • the composition comprises a vehicle in an amount of from about 15% to about 98% by weight, about 30 to about 98% by weight, about 50% to about 95% by weight, about 75% to about 95% by weight, about 80%, or about 90% by weight, based on the total weight of the composition.
  • the composition comprises a vehicle in an amount of from 15% to 98% by weight, 30 to 98% by weight, 50% to 95% by weight, 75% to 95% by weight, 80%, or 90% by weight, based on the total weight of the composition.
  • the vehicle comprises an active agent, such as comprising active agent dissolved, suspended or dispersed in the vehicle.
  • the active agent(s) in the vehicle can be the same as or different from the active agent(s) loaded onto the porous excipient.
  • the viscosity-regulating agent may be any viscosity-regulating agent suitable for use as a viscosity-regulating agent in a nasal pharmaceutical composition.
  • the viscosity-regulating agent comprises mesoporous silica (which may be loaded with active agent or unloaded).
  • the viscosity-regulating agent comprises cellulose, cellulose-containing substances, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides, lanolin, or combinations of any two or more thereof.
  • the viscosity-regulating agent comprises colloidal silicon dioxide (such as but not limited to AEROSIL® 200 (Evonik) and/or CAB-O-SIL® M5 (Cabot)).
  • the viscosity-regulating agent comprises synthetic silica, such as SYLODENT® (precipitated silica with a compacted bulk density of about 110 kg/m 3 , a specific surface area of about 190 m 27g, and an average particle size of about 18 ⁇ ) or SYLOBLANC® silicas (porous silica gel with a pore volume of about 1.6 ml/g and an average particle size of about 3 ⁇ ) from W.R. Grace & Co.
  • SYLODENT® precipitated silica with a compacted bulk density of about 110 kg/m 3 , a specific surface area of about 190 m 27g, and an average particle size of about 18 ⁇
  • SYLOBLANC® silicas porous silica gel with a
  • the viscosity-regulating agent comprises hydrophilic fumed silica, such as AEROSIL® 200 and/or lipophilic silicon dioxide, such as AEROSIL® R972 (which is fumed silica aftertreated with dimethyldichlorosilane, and which has a surface area of about 90 to about 130 m /g).
  • hydrophilic fumed silica can be used to prepare a thixotropic gel composition with a high temperature stability as compared to a comparable gel produced with other viscosity-regulating agents.
  • the viscosity-regulating agent may be present in an amount effective to adjust the viscosity of the composition to the desired level.
  • the composition comprises from about 0.5 to about 20% by weight, about 0.5 to about 10% by weight, about 0.5 to about 7% by weight, about 1 to about 4% by weight, about 4% by weight, or about 2% by weight viscosity-regulating agent, based on the total weight of the composition.
  • the composition comprises from 0.5 to 20% by weight, 0.5 to 10% by weight, 0.5 to 7% by weight, 1 to 4% by weight, 4% by weight, or 2% by weight viscosity- regulating agent, based on the total weight of the composition.
  • the composition has a viscosity as measured by a rotating viscometer of about 2,000 mPa-sec to about 10,000 mPa-sec, such as about 2,000 mPa-sec, about 3,000 mPa-sec, about 4,000 mPa-sec, about 5,000 mPa-sec, about 6,000 mPa-sec, about 7,000 mPa-sec, about 8,000 mPa-sec, about 9,000 mPa-sec, or about 10,000 mPa-sec.
  • the composition has a viscosity as measured by a rotating viscometer of 2,000 mPa-sec to 10,000 mPa-sec, such as 2,000 mPa-sec, 3,000 mPa-sec, 4,000 mPa-sec, 5,000 mPa-sec, 6,000 mPa- sec, 7,000 mPa-sec, 8,000 mPa-sec, 9,000 mPa-sec, or 10,000 mPa-sec.
  • a rotating viscometer of 2,000 mPa-sec to 10,000 mPa-sec, such as 2,000 mPa-sec, 3,000 mPa-sec, 4,000 mPa-sec, 5,000 mPa-sec, 6,000 mPa- sec, 7,000 mPa-sec, 8,000 mPa-sec, 9,000 mPa-sec, or 10,000 mPa-sec.
  • the porous excipient functions as the only viscosity-regulating agent in the composition.
  • the composition does not include a viscosity-regulating agent other than the porous excipient.
  • porous excipient having silanol groups such as but not limited to mesoporous silica such as SYLOID®
  • the porous excipient has isolated, germinal, and/or vicinal silanol groups. Even if the porous excipient comprises silanol groups, another viscosity-regulating agent may or may not be added to the composition.
  • the composition may or may not contain other components suitable for use a nasal pharmaceutical composition.
  • the composition may independently comprise one or more of: a solubilization agent; a cosolvent; a charge modifying agent; a pH control agent; an osmotic adjusting agent; a degradative enzyme inhibitor; an antioxidant; a stabilizer; a membrane penetration-enhancing agent; an emulsifying agent; a wetting agent; a suspending agent; a surfactant; an adhesive; and/or a taste-masking agent.
  • the composition independently does not contain one or more of (i.e., one or more of the following are not present in the composition): a solubilization agent; a cosolvent, a charge modifying agent; a pH control agent; an osmotic adjusting agent; a degradative enzyme inhibitor; an antioxidant; a stabilizer; a membrane penetration-enhancing agent; an emulsifying agent; a wetting agent; a suspending agent; a surfactant; an adhesive; and a taste-masking agent.
  • a solubilization agent e.e., one or more of the following are not present in the composition
  • a solubilization agent e.g., one or more of the following are not present in the composition
  • a solubilization agent e.g., one or more of the following are not present in the composition
  • a solubilization agent e.g., one or more of the following are not present in the composition
  • a solubilization agent e.g., one or
  • the porous excipient is the only excipient in the composition.
  • the surfactant may be any surfactant suitable for use as a surfactant in a nasal pharmaceutical composition.
  • the surfactant is selected from anionic, cationic, amphoteric, and non-ionic surfactants, including, but not limited to, lecithin, fatty acid esters of polyvalent alcohols, fatty acid esters of sorbitanes, fatty acid esters of polyoxyethylensorbitans, fatty acid esters of polyoxyethylene, fatty acid esters of sucrose, fatty acid esters of polyglycerol, oleoyl polyoxylglycerides (such as but not limited to apricot kernel oil PEG-6-esters), oleoyl macrogolglycerides, and/or humectants such as sorbitol, glycerine, polyethylene glycol, macrogol glycerol fatty acid ester, and combinations of any two or more thereof.
  • the surfactant is selected from anionic, cationic, amphoter
  • the surfactant if present, may be present in an amount effective to exert surfactant properties.
  • the composition comprises from about 1 to about 20% by weight, about 1 to about 10% by weight, about 1 to about 5% by weight, about 4% by weight, or about 2% by weight surfactant, based on the total weight of the composition.
  • the composition comprises from 1 to 20% by weight, 1 to 10% by weight, 1 to 5% by weight, 4% by weight, or 2% by weight surfactant, based on the total weight of the composition.
  • the composition comprises (a) from about 0.5% to about 50% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) from about 0.5% to about 40% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (c) from about 50% to about 90% w/w of castor oil, based on the weight of the composition; and (d) from about 0.5% to about 20% w/w of colloidal silicon dioxide, based on the weight of the composition.
  • the composition comprises (a) from about 0.5% to about 50% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) from about 0.5% to about 40% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (c) from about 50% to about 90% w/w of castor oil, based on the weight of the composition; and (d) from about 2% to about 6% w/w of oleoyl
  • macrogolglycerides based on the weight of the composition.
  • the composition comprises (a) from about 6% to about 11% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) from about 0.1% to about 30% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; and (c) from about 70% to about 80% w/w of castor oil, based on the weight of the composition.
  • the composition comprises from about 0.5% to about 20% of a viscosity regulating agent, based on the weight of the composition.
  • the composition comprises (a) about 8% w/w of a mesoporous silica excipient, based on the weight of the composition; (b) about 2% w/w of active agent, based on the weight of the composition, wherein the active agent is loaded onto a surface of the mesoporous silica located inside pores of the mesoporous silica; (b) about 80% w/w of castor oil, based on the weight of the composition; and (c) about 10% w/w of colloidal silicon dioxide, based on the weight of the composition.
  • the compositions comprises (a) a nasal gel containing from about 1% to about 50% w/w of mesoporous silica unloaded and/or loaded with an active agent based on the weight of the composition and (b) additional excipients up to 100% w/w of the weight of the composition.
  • nasal pharmaceutical compositions comprising a porous excipient and an active agent, wherein the active agent is loaded onto a surface of the porous excipient located inside pores of the porous excipient.
  • the active agent is loaded onto the porous excipient via one or more processes selected from fluid bed impregnation, spontaneous evaporation and
  • the active agent is loaded onto the porous excipient via oil adsorption.
  • the porous excipient is mixed with an active agent dissolved in oil, such as any one or more of plant oils, animal oils, and mineral oils.
  • oils include vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut oil, linalool, TRANSCUTOL® HP (purified diethylene glycol monoethyl ether EP/NF from Gattefosse), CAPRYOLTM PGMC (propylene glycol monocaprylate (type I) NF from
  • the oil (with dissolved active agent) and porous excipient are mixed at a volume ratio of less than about 3: 1 oil: excipient, such as about 2.5: 1 oil: excipient, about 2: 1 oihexcipient, about 1.5: 1
  • the oil (with dissolved active agent) and porous excipient are mixed at a volume ratio of less than 3: 1 oil: excipient, such as 2.5: 1 oil: excipient, 2: 1 oil: excipient, 1.5: 1 oil: excipient, or 1 : 1 oil: excipient.
  • the oil and porous excipient are mixed at a ratio of about 10: 1 oil: excipient, such as about 8: 1 or about 5: 1 oihexcipient.
  • the oil and porous excipient are mixed at a ratio of 10: 1 oil: excipient, such as 8: 1 or 5: 1 oihexcipient.
  • the active agent is loaded onto the porous excipient via a solvent, such as one or more of methylene chloride, dichloromethane, acetone, water, and ethanol.
  • the porous excipient is mixed with an active agent dissolved in a solvent, such as an ethanohwater mixture.
  • the active agent is dissolved in an ethanohwater mixture comprising about 30:70 (v/v), about 40:60 (v/v), about 45:55 (v/v), about 50:50 (v/v), about 55:45 (v/v), about 60:40 (v/v), or about 70:30 (v/v) ethanol: water.
  • ethanohwater ratios can be further varied based on the active agent used and its solubility in ethanol.
  • a release-modifying agent is used to facilitate loading of the active agent onto the porous excipient.
  • the release-modifying agent, or a solution comprising the release-modifying agent is added to the active agent mixture (e.g., the oil or solvent comprising the active agent), and then the active agent is loaded onto the porous excipient.
  • the release-modifying agent if used, may be any release-modifying agent suitable for use in loading an active agent onto a porous excipient.
  • the release-modifying agent comprises polyvinylpyrrolidone (such as but not limited to PVP K25® from Ashland, Inc., which has a.
  • a solution comprising the release-modifying agent comprises the release-modifying agent mixed in an oil (such as but not limited to one or more of and vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut oil, linalool, TRANSCUTOL® HP (purified diethylene glycol monoethyl ether EP/NF from Gattefosse), CAPRYOLTM PGMC (propylene glycol monocaprylate (type I) NF from Gattefosse)) or a solvent (such as but not limited to one or more of methylene chloride, dichlorome thane, acetone, water, and ethanol).
  • an oil such as but not limited to one or more of and vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut oil, linalool, TRANSCUTOL® HP (purified diethylene glycol monoethyl ether EP/NF from Gattefosse), CAPRYOLTM PGMC (propylene glycol monocaprylate (type I
  • the solution comprises about 0.01%, about 0.05%, about 0.1%, about 0.5%, 1%, about 2%, about 2.5%, about 3%, about 5%, about 10%, about 20%, or about 30% w/w release-modifying agent, such as 0.01%, 0.05%, 0.1%,
  • the release-modifying agent solution is added to the active agent mixture in an amount of about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 2.5%, about 3%, about 5%, or about 10%, such as 0.01 %, 0.05%, 0.1%, 0.5%, %, 2%, 2.5%, 3%, 5%, or 10%.
  • active agent is loaded onto porous excipient with a high loading efficiency. In some embodiments, at least about 60% of the active agent used in the process is loaded onto the porous excipient. In some embodiments, an active agent is loaded onto a porous excipient with a loading efficiency of at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%, including about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • an active agent is loaded onto a porous excipient with a loading efficiency of at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%, including 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the active agent is loaded onto a porous excipient with an efficiency of at least about 95% or at least 95%.
  • the active agent is loaded onto a surface of the porous excipient located inside the pores of the porous excipient. In some embodiments, loaded onto a surface of the porous excipient located inside the pores of the porous excipient, but is not loaded onto the external surface of the porous excipient.
  • Some embodiments comprise completely or partly exchanging a gelling agent (such as but not limited to fumed silica) against a porous excipient adsorbate (such as but not limited to porous silica adsorbate).
  • a gelling agent such as but not limited to fumed silica
  • a porous excipient adsorbate such as but not limited to porous silica adsorbate.
  • the active agent is loaded onto the porous excipient through interactions with active agents otherwise loaded onto the excipient, for instance through capillary forces and/or Van der Waals interactions (e.g., through interactions with active agent molecules already loaded on the porous excipient).
  • the active agent is loaded onto the porous excipient through interactions with silanol groups on the surface of the porous excipient.
  • active agent is adsorbed to the porous excipient.
  • active agent is covalently bound to the porous excipient via functional groups on the porous excipient. Without being bound by theory, it is believed that covalently bound active agent can be released in response to a stimulus, such as a change in pH, temperature, presence of enzymes, etc.
  • the porous excipient is synthesized from a precursor, such as tetraethyl orthosilicate or (3-mercaptopropyl)trimethoxysilane.
  • compositions can be prepared without formulating a thermodynamically critical suspension.
  • compositions are prepared using sterile materials. In some embodiments, compositions are prepared under sterile conditions.
  • the active agent and porous excipient are independently dissolved in an oil and/or solvent (such as ethanol, water, methylene chloride, dichloromethane, acetone, or combinations of two or more thereof) and mixed together.
  • the active agent and the porous excipient are mixed in a stepwise manner, such as by adding the active agent via pump to a stirred porous excipient.
  • the resultant mixture is dried under vacuum (such as but not limited to at a temperature from about 50°C to about 80°C).
  • the resultant solution is spray dried to obtain porous excipient loaded with active agent
  • the mixture is homogenized before spray drying.
  • the spray dried particles are spray dried a second time after mixing them with a second solution with dissolved active agent.
  • the active agent is dissolved in a solvent, and then the porous excipient is mixed into the solvent.
  • the active agent and the porous excipient are mixed in a stepwise manner, such as by adding the active agent via pump to a stirred porous excipient.
  • the resultant mixture is dried under vacuum (such as but not limited to at a temperature of from about 50°C to about 80°C).
  • the resultant mixture is spray dried.
  • the resultant mixture is spray dried after the active agent has been completely introduced into the porous excipient (e.g., after a maximum amount of active agent is loaded onto the porous excipient).
  • the loaded porous excipient is mixed with additional components, such as a vehicle, a surfactant (such as but not limited to an emulsifying agent), unloaded active agent, and a viscosity-reducing agent prior to spray drying.
  • a surfactant such as but not limited to an emulsifying agent
  • the loaded porous excipient is mixed with an emulsifying agent.
  • the emulsifying agent if present, may be any emulsifying agent suitable for use as an emulsifying agent in a nasal pharmaceutical composition.
  • the emulsifying agent comprises sodium oleate, TWEEN® 20, Natriumoleat, LUTROL® F68, or combinations of any two or more thereof.
  • the emulsifying agent may be present in an amount effective to emulsify components of the composition.
  • the compositions comprise from about 0.01 % w/w to about 2 % w/w, from about 0.02% w/w to about 1 % w/w, about 0.03% w/w, about 0.04% w/w, or about 0.08% w/w emulsifying agent, based on the total weight of the mixture.
  • compositions comprise from 0.01 % w/w to 2 % w/w, from 0.02% w/w to 1% w/w, 0.03% w/w, 0.04% w/w, or 0.08% w/w emulsifying agent, based on the total weight of the mixture.
  • the methods result in a yield of greater than 25%, such as from about 25% to about 100%, from about 50% to about 99%, about 60% to about 98%, about 70% to about 95%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99%. In some embodiments, the methods result in a yield of from 25% to 100%, from 50% to 99%, 60% to 98%, 70% to 95%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%. [0156] In some embodiments, a coating is added to the loaded porous excipient.
  • the material used to prepare the coating is dissolved in a solvent, and then a loaded porous excipient is added to the solution.
  • active agent and the coating material are independently dissolved in an oil and/or solvent (such as ethanol, water, methylene chloride, dichloromethane, acetone, or combinations of two or more thereof), mixed together, and then a loaded porous excipient is added to the resultant solution.
  • the solution with both loaded porous excipient and coating material can then be spray dried.
  • the coating material and loaded porous excipient are spray dried together without being mixed together first.
  • the porous excipient loaded with active agent is coated as described above via spray-drying or co-processing together with a coating substance (e.g., polymers insoluble in oil or other substances described above).
  • a coating substance e.g., polymers insoluble in oil or other substances described above.
  • the loaded porous excipient and coating substance are spray dried in a one-phase system.
  • the loaded porous excipient and coating material are spray-dried in an emulsion.
  • the coated porous excipient loaded with active agent is mixed with additional components, such as a vehicle, a surfactant, unloaded active agent, and a viscosity- enhancing agent.
  • the loaded pores are capped, for example, to inhibit or control release of the active agent from the pores.
  • the pores can be capped by any suitable method, such as by covalently bonding nanocrystals (such as but not limited to cadmium sulfide nanocrystals) to the pore entrances. Exemplary methods of pore-capping are discussed in Lai et al, . Am. Soc. Chem. 125(15): 4451-4459 (2003) and Sun, "Mesoporous silica nanoparticles for applications in drug delivery and catalysis," graduate Theses and Dissertations, Paper 12812 (2012), both of which are incorporated herein by reference.
  • a composition as described herein comprising a therapeutically effective amount of an active agent is nasally administered to a subject in need thereof, such as by applying an amount of the composition to the nasal cavity or administering an amount of the composition into the nasal cavity.
  • the composition may be administered from any device suitable for administering nasal compositions, such as a multi-dose device or a single-dose device.
  • the compositions achieve therapeutic levels of the active agent in blood and/or brain for up to 2 hours post-administration, up to 3 hours post-administration, up to 4 hours post-administration, up to 5 hours post-administration, or up to 6 hours post- administration. In some embodiments, the compositions achieve therapeutic levels in the blood and/or brain for 6 hours or more.
  • compositions described herein depend on the active agent(s) formulated in the composition. Intranasal delivery may be particularly useful for treating disorders of the central nervous system (such as but not limited to spina bifida), disorders of the brain, and/or disorders of the spinal cord. In some embodiments, compositions described herein are useful in methods of treating neurological or psychiatric disorders.
  • compositions described herein are useful in methods of treating: diseases caused by faulty genes, such as Huntington's disease or muscular dystrophy; degenerative diseases, such as Parkinson's disease or Alzheimer's disease; diseases related to blood vessels, such as stroke; injuries to the spinal cord and/or brain; seizure disorders, such as epilepsy; cancer, such as brain tumors; and infections, such as meningitis.
  • diseases caused by faulty genes such as Huntington's disease or muscular dystrophy
  • degenerative diseases such as Parkinson's disease or Alzheimer's disease
  • diseases related to blood vessels such as stroke
  • injuries to the spinal cord and/or brain disorders to the spinal cord and/or brain
  • seizure disorders such as epilepsy
  • cancer such as brain tumors
  • infections such as meningitis.
  • compositions described herein comprising testosterone are useful in methods of treating hypogonadism (such as primary hypogonadism or secondary hypogonadism), female sexual dysfunction, female arousal disorder, anorgasmia, or hypoactive sexual desire disorder, Multiple sclerosis (MS).
  • hypogonadism such as primary hypogonadism or secondary hypogonadism
  • progesterone is useful in methods of treating insomnia and brain injuries.
  • compositions described herein comprising aripiprazol, auetiapin, or paliperidon are useful in methods of treating schizophrenia.
  • compositions described herein comprising duloxetine or dopamine are useful in methods of treating depression and/or anxiety.
  • compositions described herein comprising testosterone, glatirameracetat, interferon beta- la, interferon beta- lb, fingolimod, natalizumab, or dimethylfumarat are useful in methods of treating multiple sclerosis.
  • compositions described herein comprising pregnenolone, memantine, rivastigmin, or donepezil are useful in methods of enhancing memory or treating Alzheimer's disease.
  • compositions described herein comprising desvenlafaxine, duloxetine, or dopamine are useful in methods of treating depression.
  • compositions described herein comprising eszopiclone or eszopiclone are useful in methods of treating insomnia.
  • compositions described herein comprising tomoxetin, guanfacine, methylphenidate, lisdexamfetamine, or dopamine are useful in methods of treating attention deficit hyperactive disorder.
  • compositions described herein comprising progesterone or recombinant tissue plasminogen activator (rt-PA) are useful in methods of treating traumatic brain injury.
  • compositions described herein comprising methotrexate, raltitrexed, 5- fluorouracil, telomerase inhibitor, or monoclonal antibodies are useful in methods of treating a brain tumor.
  • compositions described herein comprising midazolam, lacosamide, levetiracetam, lamotrigine, or valproic acid are useful in methods of treating epilepsy.
  • compositions described herein comprising oxycodone, pregabalin, buprenorphine, hydrocodone, or fentanyl are useful in methods of treating pain.
  • compositions described herein comprising safinamide, ropinirole, pramipexole, dopamine, L-DOPA, selegiline, cabergoHne, or istradefylline are useful in methods of treating Parkinson's disease.
  • compositions as described here can be used to vaccinate a subject.
  • compositions as described herein can be used to vaccinate a subject against influenza, hepatitis B, or meningitis.
  • Example 1 Testosterone-loaded beads: Loading via spray drying
  • Spray dried testosterone-loaded beads were prepared using the following protocol. First Spray Drying Step
  • Table 1 A Spray-drying parameters for first spray-drying step in testosterone loading experiment
  • the spray dried particles were collected in a high efficiency cyclone, and then dried in a vacuum drying oven at 40°C and 10 mbar for six days.
  • the dispersion was spray dried using a Mini Spray Dryer B-290 (Biichi) with a standard two-fluid nozzle with a 0.7 mm diameter nozzle tip, which was operated in closed- loop mode with nitrogen as the dispersion gas (inert loop B-295). The instrument was run in sucking mode. During spray drying, the dispersion was stirred at 500 rpm. Spray drying parameters are set forth in Table IB.
  • Table 1 B Spray-drying parameters for second spray-drying step in testosterone loading experiment
  • the final testosterone-loaded particles were dried in a vacuum drying oven at 40°C and 10 mbar.
  • the particles have a theoretical loading of 22.9% testosterone.
  • Example 2 Testosterone-loaded particles: Free-flowing powder
  • a free-flowing powder of testosterone-loaded particles was prepared using the following protocol. [0173] 0.2143 g of testosterone were added to 1.5 g of linalool oil and then mixed using a vortex mixer for 10 minutes. Then, 0.5 g of SYLOID® particles (both 244FP and XDP3050 were used in independent experiments) were added to 0.75 g of the dissolved testosterone mixture, which was then stirred with a magnetic stirrer at 700 rpm for 10-15 minutes. The SYLOID® / testosterone mixture was then mixed with a spatula to reintroduce portions of the mixture adhered to the wall of the mixing container, and then stirred again with a magnetic stirrer for 10-15 minutes. The particles have a theoretical loading of about 7.5% testosterone.
  • Example 3 Testosterone-loaded particles: Free-flowing powder, loading by oil adsorption method
  • Testosterone-loaded particles were prepared using the following protocol.
  • 0.2143 g of testosterone was added to 1.5 g of linalool oil and then mixed using a vortex mixer for 10 minutes. Then, 0.5 g of SYLOID® particles (both 244FP and 72FP were used in independent experiments) were added to 1.5 g of the dissolved testosterone mixture, which was then stirred with a magnetic stirrer at 700 rpm for 10-15 minutes. The SYLOID® / testosterone mixture was then mixed with a spatula to reintroduce portions of the mixture adhered to the wall of the mixing container, and then stirred again for a magnetic stirrer for 10- 15 minutes. The particles have a theoretical loading of about 9.4% testosterone.
  • Example 4 Progesterone-loaded beads: Loading via spray drying
  • Spray dried progesterone-loaded beads were prepared using the following protocol.
  • the mixture was spray dried using a Mini Spray Dryer B-290 (Buchi) with a standard two-fluid nozzle with a 0.7 mm diameter nozzle tip, which was operated in closed-loop mode with nitrogen as the dispersion gas (inert loop B-295).
  • the instrument was run in sucking mode. During spray drying, the dispersion was stirred at 500 rpm. Spray drying parameters are set forth in Table 2.
  • the spray dried particles were collected in a high efficiency cyclone, and then dried in a vacuum drying oven at 40°C and 10 mbar for six days.
  • the particles have a theoretical loading of about 40% progesterone.
  • Spray dried progesterone particles were prepared using the protocol set forth in Example 4, but with component amounts varied to produce particles with theoretical loadings of 30%, 40%, 50%, and 60% progesterone. Yields were determined based on the mass of the composition after spray drying into a vial as compared to the combined mass of the progesterone and SYLOID® particles before spray drying. Residual moisture was calculated as a change in mass after vacuum drying the spray dried particles.
  • Table 3 A S ray dried compositions with progesterone + SYLOID® 72FP.
  • Spray dried particles were also prepared using a similar protocol, but with SYLOID® 244FP instead of SYLOID® 72FP. These compositions are set forth in Table 3B.
  • Table 3B Spray dried compositions with progesterone + SYLOID® 244FP.
  • compositions with SYLOID® 72FP or SYLOID® 244FP but without progesterone were prepared via spray drying. These compositions are set forth in Figure 3C.
  • the progesterone reference composition was spray dried with a Mini Spray Dryer B-290 (Biichi) with a two-fluid nozzle in the closed cycle system.
  • the settings were constant with the aspirator rate at 100%, spray gas flow at 45 mm, pump rate at 10%, nozzle cleaner at 1, and Tj n a 81°C.
  • the yield was determined to be 17.3% by comparing the weight of an empty glass vial to the glass vial containing spray dried particles.
  • Scanning electron micrographs of the progesterone reference which are provided in Figure 4, were obtained to examine the morphology and size of the particles. The scanning electron micrographs were taken at two separate focal lengths; in the sub-figure on the left side of Figure 4, the bar represents a 10 ⁇ distance, and in the sub-figure on the right side of Figure 4, the bar represents a 1 ⁇ distance.
  • melting points (peak temperature), glass transition temperature (onset), and recrystallization (peak temperature) of the two heating cycles were determined and are set forth in Table 5.
  • Table 5 Thermal behavior of progesterone from DSC curves obtained with reference samples.
  • Progesterone was impregnated on ordered mesoporous silica (OMS-7) powder using either 200 mg/ml solutions of progesterone in methylene chloride or 100 mg/ml solutions of progesterone in acetone to obtain loadings of 30%, 35%, and 40% (w/w) progesterone.
  • OMS-7 ordered mesoporous silica
  • the total surface area was calculated via the Brunauer-Emmett-Teller (BET) model.
  • the data indicate a progressive decrease in pore diameter with loading, indicative of layer wise deposition of progesterone onto the OMS-7 surface.
  • progesterone is interacting with both the OMS-7 and also with other progesterone moieties, for instance through capillary forces or Van der Waals interactions.
  • Table 6 Porosity Data from nitrogen physisorption experiments.
  • Testosterone was impregnated on ordered mesoporous silica (OMS-7) powder using either 200 mg/ml solutions of testosterone in methylene chloride or 100 mg/ml solutions of testosterone in ethanol to obtain loadings of 30%, 35%, and 40% (w/w) testosterone.
  • OMS-7 ordered mesoporous silica
  • Progesterone gel compositions with encapsulated progesterone were prepared as set forth in Table 8.
  • additional colloidal anhydrous silica was added to improve viscosity, resulting in a composition with component amounts that exceed 100% (the % weights in Composition 1 total 102%).
  • Testosterone gel compositions with encapsulated testosterone were prepared as set forth in Table 9. Table 9: Testosterone Gel Compositions
  • compositions were prepared with testosterone encapsulated in the presence of the following polymers: polylactide, chitosan, or gelatin.
  • Table 1 1 Parameters of spray-drying experiments with polylactide and resulting yields.
  • MetP 85 was prepared analogously to MetP 75, but in duplicate batch size.
  • the yield was increased from 4.8% to 25.3% by increasing the PLA quantity added, and from 25.3% to 63.8% by additionally reducing the entry temperature T ln .
  • T ln entry temperature
  • a chitosan solution was formed by dissolving 0.5 g of pharmaceutical-grade chitosan 95/200 (deacetylation level 95%, viscosity in 1% acetic acid: 151-350 mPa) in 50 ml of 2% acetic acid.
  • 50 ml of ethanol was added to the chitosan solution.
  • testosterone compositions 48 ml of ethanol was added to the chitosan solution; testosterone was dissolved in 2 ml of ethanol, and then added to the chitosan/ethanol solution.
  • the solutions were spray-dried in a Mini Spray Dryer using a two-fluid nozzle in a closed system of suction and stir speed of 200 rpm.
  • Dryer settings were as follows: entry temperature 140°C, 10% pump power, 100% aspirator power, dispersion gas at 50 mm and the nozzle cleaner at 1 remained constant. Yields obtained with these experiments are set forth in Table 12. Table 12: Parameters of spray-drying experiments with ehitosan and their resultant yields.
  • the yields of the particles produced were between 60.0% and 72.4%.
  • the morphology of the particles are shown in the SEM images of Figure 16, which shows particles with a broad distribution of sizes.
  • TPP tripolyphosphate
  • gelatin was dissolved in water and sprayed as (i) a single-phase or (ii) an emulsion of water and dichlorome thane.
  • MetP_08 to MetP_10 in Table 13A 0.5 g of gelatin each was dissolved in 50 mL of water; for MetP_l 1 to MetP_13 in Table 13 A, 0.5 g of gelatin each was dissolved in 47.5 mL of water.
  • the mixtures were agitated in an incubating shaker at 37 °C to achieve complete dissolution and subsequently brought to room temperature.
  • MetP_l l to MetP_13 0.175 g of TWEEN® 20 and 2.5 mL of dichloromethane was also added. The mixtures were subsequently homogenized by a rotor/stator set-up for 10 minutes at 30,000 rpm while cooling it by means of ice.
  • Table 1 A Overview of gelatin particles spray-dried in a one -phase system in comparison to spray-dried in emulsion.
  • Yields depended on the type of system to be sprayed; thus, the yields for gelatin particles spayed in emulsion were lower than for gelatin particles sprayed as single-phase. Without being bound by theory, it is believed that a reduction of emulsifier content might lead to an increase in yield.
  • Emulsifiers LUTROL® F68 and sodium oleate were tested as substitutes for
  • TWEEN® 20 in compositions obtained with F25 gelatin. Casein was also tested as an emulsifier, but it did not dissolve in either water or dichloromethane.
  • the parameters of the Mini Spray Dryer remained unchanged from the last experiments and the variable parameters are shown in Table 13B.
  • Table 13B Parameters of the spray-drying experiments in emulsion with variable emulsifier and variable amount of emulsifier and the resulting yields.
  • compositions in a single phase are provided.
  • compositions were sprayed in various ethanol/water mixtures.
  • Gelatin solutions were sprayed in ethanol/water mixtures with ratios of 40/60 (v/v), 45/55 (v/v), and 50/50 (v/v). All gelatin batches were stable in the 40/60 and 45/55 mixtures.
  • F15 gelatin was also stable at 50/50 (v/v), but the F20 and F25 gelatin— previously dissolved in water— precipitated out of solution at the 50/50 (v/v) ratio.
  • Table 14 used 0.5 g gelatin.
  • Differing quantities of water were added to the gelatin for the differing mixing ratios (20 mL for 40/60, 22.5 mL for 45/55, and 25 mL for 50/50). Dissolution of the gelatin took place at 37°C in an incubating shaker at 200 rpm for a period of at least an hour. The solution was then brought to room temperature by stirring in a magnet stirrer at 500 rpm, and each of the necessary quantities of ethanol for establishing the correct mixing ratio was added. For loading of testosterone, a small quantity of ethanol was added to the gelatin solution and then the dissolved testosterone was added to obtain the correct mixing ratio.
  • Table 14 Parameters of the spray-drying experiments with gelatin in different ethanol-water mixtures.
  • Figures 19A-E show the SEM images of the gelatin particles that were sprayed in ethanol/water.
  • the particles produced in the ethanol/water 40/60 (v/v) mixture no clear differences were observed in the particle size distributions between the various experimental approaches. Only the particles from the unloaded approach using F15 gelatin (MetP_29) appeared to be somewhat smaller in size.
  • Bacteria were detected in the SEM images of the testosterone-loaded particles produced with the 45/55 (v/v) ethanol/water mixture (MetP_56, MetP_43 and MetP_44), highlighting the importance of using sterile gelatin under sterile conditions.
  • Compositions produced in ethanol/water 50/50 (v/v) show no significant differences compared to those particles produced using the other mixing ratios.
  • Example 14 Loading of testosterone in porous silica niicroparticles
  • Various mesoporous silica particles (SYLOID®, from Grace) were used to encapsulate testosterone. Properties of the mesoporous silica particles are shown in Table 15. The morphology of the particles are shown in the SEM images of Figures 20A-B. Table 15: SYLOID® particles, particle size, pore volume and specific surface area.
  • the active agent testosterone originated from two separate batches (termed “first delivery” and “second delivery”). Loading experiments were carried out with both of the deliveries. SYLOID® particles were dispersed in ethanol at a level of 1% (i.e. 1 g to 100 mL). In compositions with testosterone, the testosterone (either 10% or 30% in relation to the total mass, i.e. testosterone + SYLOID®) was dissolved in a portion of the ethanol, and then subsequently added to the particle dispersion system. The particle mixtures were stirred with a magnetic stirrer at 500 rpm, and then sprayed with a two-fluid nozzle in a closed suction system using the B-290 Mini Spray Dryer (Buchi).
  • Table 16 Parameters of the spray-drying experiments with SYLOID® particles and their yields.
  • MetP_79A to MetP_79C the incubation period of the SYLOID® particles with testosterone was varied prior to spray drying to allow additional time for adsorption of the testosterone if needed.
  • MetP_62 and MetP_62A were spray dried under analogous conditions, and they demonstrate a high level of reproducibility of the spray drying process. The yields were 66.0% and 66.2%, respectively.
  • Testosterone Second Delivery (i.e.. Second Batch)
  • SYLOID® 244FP particles and AEROSIL® 200 particles were used to encapsulate testosterone.
  • the SYLOID® particles or AEROSIL® particles were dispersed in ethanol at a level of 1% (i.e. 1 g to 100 mL).
  • the testosterone either 30% or 40% in relation to the total mass, e.g., testosterone + SYLOID®
  • the particle mixtures were stirred with a magnetic stirrer at 500 rpm, and then sprayed with a two- fluid nozzle in a closed suction system using the B-290 Mini Spray Dryer (Biichi).
  • the entry temperature was varied and dropped to 81 °C.
  • a 50/50 ethanol/water mixture (v/v) was used as a continuous phase in place of ethanol to increase the adsorption of the testosterone if needed.
  • the parameters of the Mini Spray Dryer remained constant with 10% pump power, 100% aspirator power, dispersion gas at 45 mm and the nozzle cleaner at 1.
  • the solution was stirred at 200 rpm during the spraying process.
  • the variable parameters are shown in Table 17.
  • Table 17 Parameters of the spray-drying experiments with testosterone (second delivery) and their yields.
  • a particle/oil ratio of 1: 1.5 was employed for testosterone loading the SYLOID® particles by means of oil. 0.75 g of each oil loaded with testosterone and 0.5 g of each of the SYLOID® particles were mixed and stirred with a magnetic stirrer at 700 rpm for ten minutes The mixture was also manually mixed with a spatula, and then stirred again for 10 minutes at 700 rpm. Properties of different compositions are set forth in Table 20.
  • Table 20 Experimental batches of different particle / oil mixtures in a ratio of 1 : 1.5.
  • the SYLOID® XDP6035 particles did not adsorb the oil completely and formed a sticky mass, perhaps due to their small pore volumes.
  • the SYLOID® 244FP and XDP3050 particles were powder-like after testosterone loading.
  • Figure 24 demonstrates the textures of the compositions in Table 20.
  • Core/shell particles of mesoporous silica particles and gelatin were synthesized to assess the ability to prepare particles with an enhanced retardation effect (i. e. , delayed release of testosterone). Without being bound by theory, it is believed that unloaded gelatin can function as a barrier to delay testosterone release, while with testosterone-loaded gelatin, the gelatin can act as a substrate for the testosterone.
  • the particles were spray dried using a Mini Spray Dryer in a closed system in suction while stirring was continued at 500 rpm on the magnetic stirrer.
  • the entry temperature Tj n of 135°C, the dispersion gas 45 mm, aspirator power level 100%, pump power level 10% and the nozzle cleaner at 1 were constant.
  • the variable parameters are shown in Table 22.
  • Table 22 Parameters and results of the spray-drying experiments by using the two-fluid nozzle.
  • SYLOID® 244FP particles primarily spherical particles were formed by spray drying in the presence of gelatin. Very few particles still displayed open pores, and irregularly shaped SYLOID® particles were evident to a small extent. It is believed that coating was successfully achieved through employment of the gelatin.
  • F15 gelatin was dissolved in a 45/55 (v/v) solution of ethanol and water. 82.5 mL of water was first added and the gelatin solution and shaken in an incubating shaker at 37°C until completely dissolved. Then 67.5 mL of ethanol with 0.375 g of testosterone were added and stirred.
  • the SYLOID® particle suspension (core) was transported via an external pump while the gelatin solution (shell) was transported via an internal pump to the three-fluid nozzle. 50 mL of "core” solution was employed for each 150 mL of "shell” solution; excess shell solution was synthesized so that about 45 mL remained after spraying. For MetP_72, the solutions were sprayed via the corresponding other pump.
  • Table 23 Parameters and results of the spray-drying experiments by using the three-fluid nozzle.
  • the MetP_66 and MetP_72 possessed larger fragments (SYLOID® XDP6035 particles) and smaller gelatin particles.
  • the open-pore structure of the SYLOID® particles was still present, even for the smaller SYLOID® 244FP particles ⁇ see MetP_65, MetP_76, and MetP_77). The extent to which the particles were nevertheless coated by the gelatin was not assessed.
  • Particle sizes were measured for various compositions prepared in accordance with some of the preceding examples.
  • the Scirocco dry measurement cell offers a means of surveying samples in the form of powder, but the necessary sample sizes are quite large and the measurement method is therefore unsuitable for our purposes.
  • particle sizes were determined with the Mastersizer 2000 (Malvern). These compositions are shown in Table 24. Polylactide particles could not be characterized by means of the Mastersizer due to the dispersion behavior in ethanol. Samples were dispersed in ethanol and surveyed in the Hydro 2000 ⁇ dispersion measurement cell (pump speed 2500 rpm, ultrasound 30%). Without being bound by theory, it is believed that the particles are in a swollen state caused by their dispersion in ethanol, thus impacting the observed particles sizes.
  • Nasal gels were prepared using castor oil, testosterone, LABRAFIL®, and
  • AEROSIL® 200 AEROSIL® 200.
  • castor oil and the corresponding quantities of testosterone, LABRAFIL®, and AEROSIL® 200 were added in sequence.
  • the gels were produced by means of either a rotor/stator (up to 100 g) or in a ball mill (Precellys, 1-4 g). Experiments were also conducted with the Dispermat, which offers the means of preparing gels in the range of 30-40 g (data not shown).
  • Various quantities of nasal gel were prepared through the various dispersion avenues.
  • Nasal gels were initially prepared according to the nasal gel formula in Table 26.
  • Table 26 Recipe of initial nasal gel composition.
  • the content of various prepared nasal gel compositions is shown in Table 27. Larger quantities were prepared by homogenizing with a rotor/stator mixing apparatus (nasal gel 03). Each sample was mixed at 13,000 rpm for 2 x 2 minutes following the addition of testosterone and LABRAFIL®. Following the addition of AEROSIL® 200, pre-mixing was carried out first using a glass rod and afterwards by homogenizing at 13,000 rpm for a total of 20 minutes.
  • Table 27 Amounts of components in compositions prepared without SYLOID® particles
  • Nasal gel lot 07 (A) in Table 29 was prepared according to the nasal gel formula 28. SYLOID® particles were used to prepare nasal gel lots 07 (B) and 07 (C).
  • Nasal gels with testosterone-loaded porous particles were formulated with 11 mg of testosterone adsorbate (6.75 mg in solution and 4.25 mg from adsorbate). The formula is set forth in Table 30, where the total quantity was held constant. Table 30: Recipe of nasal gel (constant total volume).
  • Nasal composition preparation must balance competing concerns: maintaining a constant total quantity versus maximizing active agent solubility. If the total quantity is held constant, incorporating the SYLOID® particles would reduce the quantity of castor oil added, which could impact solubility of the testosterone in castor oil. On the other hand, if the quantity of castor oil remains constant (and solubility of testosterone is not impacted), the addition of the SYLOID® would make it so the proportions would not remain constant, thereby altering the composition recipe.
  • nasal gels having constant quantities of castor oil were prepared under this feasibility study as a first step. These compositions are shown in Table 31 and were synthesized using a ball mill (Precellys).
  • Table 3 1 Nasal gel compositions with constant castor oil quantity.
  • compositions in in Table 31 all components of the nasal gels were held constant with respect to their masses except the matrix of the loaded particles.
  • Composition 10.4 used SYLOID® 244FP particles theoretically loaded with 30% testosterone and subsequently coated with gelatin (MetP_88).
  • Composition 10.5 used SYLOID® 244FP particles theoretically loaded with 30% testosterone (MetP_86).
  • Loaded F15 gelatin particles (MetP_87, theoretical loading level 20%) were used in composition 10.6, while PLA
  • Nasal gel 11 with a formula shown in Table 32, was prepared as a reference, i.e. without addition of particles loaded with active ingredients (thus without adsorbate).
  • Table 32 Composition for reference nasal gel.
  • Table 33 Nasal gel compositions.
  • the thermal prehistory is influenced by the processing procedure - spray drying in this case - and can be discerned from the differences between the first and second heating curves.
  • the second heating curve thereby provides the initial material specific data. In this project, however, the first heating
  • Polylactide (PLA) is an amorphous polymer and therefore there is no melting peak present for this polymer. Only a glass transition in the neighborhood of 50 °C was detected, as shown in Figure 33.
  • the DSC curves of both PLA samples differ only slightly in the first heating; however, no difference was established in the curves for the second heating.
  • For the testosterone-loaded particles a somewhat different procession in the curves is evident for the first heating.
  • a broad melting peak and a recrystallization peak are detectable; however, these are shifted somewhat in comparison to pure testosterone (melting peak maximum at 146 °C and recrystallization peak maximum at 73.5 °C).
  • the presence of the melting peak for testosterone shows that this active agent is still present in crystalline form after spray drying.
  • MetP_87 For the testosterone-loaded mesoporous silica particles (SYLOID® 244FP), no testosterone melting peak in the neighborhood of 150°C could be detected either for the first or second heating, which is evident from the DSC curves in Figure 35. All curves here displayed a broad endothermic peak as well that likely emerges analogous to gelatin on account of evaporation of adsorbed water.
  • testosterone was not present in crystalline form, but instead amorphous (this could be substantiated through further investigations, e.g., synthesis of testosterone and SYLOID® mixtures, and employment of higher testosterone proportions analogous to the procedure with progesterone).
  • Non-porous silica particles (AEROSIL® 200) were spray-dried as references both as pure particles and in the presence of testosterone (theoretical loading level of 30%).
  • the DSC curves of these samples are shown in Figure 37. A small, somewhat broader melting peak just below 150°C for the loaded particles is evident here. This is also understandable, since the primary particles do not exhibit a porous structure.
  • testosterone were evaluated.
  • the loading of testosterone in polymeric matrices by means of spray drying is feasible. Specifically, loading levels of approx. 30% and yields of approx. 50% were achieved by means of RESOMER® 202H particles. Likewise, loading levels of approx. 30% and yields of approx. 70% were achieved with chitosan 95/500 as an encapsulating material. F15 gelatin was also loaded with approx. 20% testosterone and achieved a yield of 30%.
  • Mesoporous silica particles were also able to be loaded by means of spray drying, e.g., with SYLOID® 244FP particles. Loading levels of approx. 40% and yields of approx. 70% were achieved.
  • the SYLOID ® 244FP particles can likewise be loaded by means of oil;
  • the loading level was limited to 9.4% on account of the relatively poor solubility of testosterone in linalool.
  • Coating of the particles was carried out with a two-fluid nozzle as well as with a three- fluid nozzle.
  • SYLOID ® 244FP particles were employed as the core material and F15 gelatin as the coating material, achieving a loading level of about 23%.
  • a yield of 90% was achieved by means of a two-fluid nozzle, while a yield of 60% was achieved by means of a three-fluid nozzle.
  • compositions were further scaled up using the protocol discussed above. In particular, compositions with a 800 g batch size were produced, as shown in Table 34.
  • Table 34 Compositions with testosterone + SILSOLTM6035
  • compositions were prepared using SILSOL liV1 6035 in accordance with Example 18. Compositions were stored for 1 month at either 25 °C / 60% relative humidity or 30°C / 65% relative humidity. Stability of the compositions following 1 month of storage were tested via differential scanning calorimetry. In all cases, degradation- related impurities in the compositions remained substantially unchanged after 1 month of storage. Moreover, the crystalline testosterone ratio (e.g. , the percentage of testosterone that is in the crystalline state) in both formulations could be assumed to be below 0.5% by release, even after 1 month of storage. Moreover, the composition contained substantially no crystalline polymorphs of testosterone.

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Abstract

L'invention concerne des compositions pharmaceutiques nasales comprenant un excipient poreux et un agent actif, l'agent actif étant chargé sur une surface de l'excipient poreux située à l'intérieur des pores de l'excipient poreux, et la composition étant conçue pour être administrée par voie nasale. L'invention concerne également des procédés de fabrication et d'utilisation desdites compositions pharmaceutiques.
PCT/IB2017/053288 2016-06-03 2017-06-02 Compositions pharmaceutiques nasales à excipient poreux Ceased WO2017208209A1 (fr)

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JP2019516293A JP7542309B2 (ja) 2016-06-03 2017-06-02 多孔性賦形剤を含む経鼻用医薬組成物
CN201780047958.8A CN109803663A (zh) 2016-06-03 2017-06-02 具有多孔赋形剂的鼻用药物组合物
KR1020197000033A KR102387241B1 (ko) 2016-06-03 2017-06-02 다공성 부형제를 갖는 비강용 약제학적 조성물
CA3026041A CA3026041A1 (fr) 2016-06-03 2017-06-02 Compositions pharmaceutiques nasales a excipient poreux
EA201892595A EA201892595A1 (ru) 2016-06-03 2017-06-02 Назальные фармацевтические композиции с пористым наполнителем
EP17731299.8A EP3463375A1 (fr) 2016-06-03 2017-06-02 Compositions pharmaceutiques nasales à excipient poreux
SG11201810628XA SG11201810628XA (en) 2016-06-03 2017-06-02 Nasal pharmaceutical compositions with a porous excipient
AU2017274649A AU2017274649B2 (en) 2016-06-03 2017-06-02 Nasal pharmaceutical compositions with a porous excipient
MX2018014906A MX389588B (es) 2016-06-03 2017-06-02 Composiciones farmaceuticas nasales con un excipiente poroso.
ZA2018/08551A ZA201808551B (en) 2016-06-03 2018-12-19 Nasal pharmaceutical compositions with a porous excipient
JP2022067716A JP7571078B2 (ja) 2016-06-03 2022-04-15 多孔性賦形剤を含む経鼻用医薬組成物

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US12030980B2 (en) 2021-02-01 2024-07-09 Massachusetts Institute Of Technology Reprocessable compositions
US12054570B2 (en) 2019-11-15 2024-08-06 Massachusetts Institute Of Technology Functional oligomers and functional polymers including hydroxylated polymers and conjugates thereof and uses thereof
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JP2021000481A (ja) * 2020-09-15 2021-01-07 株式会社三洋物産 遊技機
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CN112972428B (zh) * 2021-03-09 2022-03-08 石河子大学 两性离子聚合物膜包覆的介孔硅基药物载体及制备方法
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CN112512505A (zh) * 2018-04-17 2021-03-16 马特恩制药股份公司 用于鼻内递送孕烯醇酮的组合物和方法
JP2021522170A (ja) * 2018-04-17 2021-08-30 エム エ ペ ファルマ アクチェンゲゼルシャフト プレグネノロンの鼻腔内送達のための組成物および方法
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US12054570B2 (en) 2019-11-15 2024-08-06 Massachusetts Institute Of Technology Functional oligomers and functional polymers including hydroxylated polymers and conjugates thereof and uses thereof
US12365752B2 (en) 2019-11-15 2025-07-22 Massachusetts Institute Of Technology Functional oligomers and functional polymers including hydroxylated polymers and conjugates thereof and uses thereof
US11737980B2 (en) 2020-05-18 2023-08-29 Orexo Ab Pharmaceutical composition for drug delivery
US12357573B2 (en) 2020-05-18 2025-07-15 Orexo Ab Pharmaceutical composition for drug delivery
US12030980B2 (en) 2021-02-01 2024-07-09 Massachusetts Institute Of Technology Reprocessable compositions
US11957647B2 (en) 2021-11-25 2024-04-16 Orexo Ab Pharmaceutical composition comprising adrenaline
US12303472B2 (en) 2021-11-25 2025-05-20 Orexo Ab Pharmaceutical device for use in intranasal administration
US12472154B2 (en) 2021-11-25 2025-11-18 Orexo Ab Pharmaceutical composition comprising adrenaline

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